Opioid Use Disorder
Conditions
Brief summary
This is a Phase 1, single-centre, randomized, double-blind, placebo-controlled, 2 fixed sequences, multiple dose study in healthy male and/or female recreational opioid users. This study is being primarily conducted to assess the effect on respiratory drive of morphine administered after multiple doses of AZD4041 compared to morphine administered alone in healthy recreational opioid users. The study will include up to 44 participants who will be randomized to either AZD4041 and morphine (28 participants) or placebo and morphine (16 participants). This is to ensure completion of at least 36 participants (24 AZD4041 + morphine, and 12 Placebo + morphine on Day 15). The total study duration will be up to 54 days (including screening) per participant.
Interventions
DRUGMorphine
Participants will receive IV dose of Morphine as stated in arm description.
DRUGAZD4041
Participants will receive oral doses of AZD4041 as stated in arm description.
OTHERPlacebo
Participants will receive oral doses of placebo as stated in arm description.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Recreational opioid user, not currently considered to have moderate or severe substance use disorder for opioids (based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition \[DSM-5\] criteria) and has experience with opioid use for non-therapeutic purposes (ie, for psychoactive effects) on at least 10 occasions in their lifetime and at least 1 occasion in the last 12 weeks prior to screening. 2. Provision of signed and dated informed consent form (ICF) prior to the initiation of any protocol-specific procedures. 3. Stated willingness to comply with all study procedures and availability for the duration of the study. 4. Healthy adult male or female, 18 to 55 years of age, inclusive, prior to the first study drug administration. 5. Body mass index (BMI) within 18.0 kg/m\^2 to 35.0 kg/m\^2, inclusive, and body weight at least 50 kg at screening. 6. A female study participant of non-childbearing potential must meet 1 of the following criteria: (1) Physiological postmenopausal status, defined as the following: 1. absence of menses for at least 1 year prior to the first study drug administration (without an alternative medical condition); and 2. Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at screening AND/OR (2) Surgical sterile, defined as those who have had hysterectomy, bilateral oophorectomy and/or bilateral salpingectomy, or bilateral tubal ligation. Women who are surgically sterile must provide documentation of the procedure by an operative report, ultrasound, or other verifiable documentation. 7\. If male, must agree to use a highly effective method of contraception when engaging in sexual activity and must not donate sperm during the study and for at least 4 months (120 days) after the last dose of study medication. 8\. Healthy in the opinion of an Investigator, as determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs, SpO2, respiratory rate, or clinical laboratory (including hematology, coagulation, clinical chemistry, urinalysis, and serology \[screening visit only\]) at screening visit and/or prior to the first study drug administration.
Exclusion criteria
1. Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration. 2. Male participants with a history of oligospermia or azoospermia or any other disorder of the reproductive system. 3. Male participants who are undergoing treatment or investigation for infertility. 4. History of moderate or severe substance or alcohol use disorder (excluding nicotine and caffeine) within the past 2 years, as defined by the DSM-5. 5. History of any significant psychiatric disorder according to the criteria of the DSM-5 which, in the opinion of the Investigator, could be detrimental to participant safety or could compromise study data interpretation. 6. History of significant hypersensitivity to AZD4041, morphine and/or other opioids, naloxone, or any related products (including excipients of the study formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs. 7. History of any significant disease, including \[but not necessarily limited to\] significant hepatic, renal, cardiovascular, pulmonary, hematologic, neurological, psychiatric, gastrointestinal, endocrine, immunologic, ophthalmologic, or dermatologic disease of any etiology (including infections) identified at screening. 8. Presence or history of significant gastrointestinal, liver or kidney disease, or any other condition \[including those that may result from surgery\] that is known to interfere with drug absorption, distribution, metabolism, or excretion, or known to potentiate or predispose to undesired effects. 9. SpO2 below 95% at screening or prior to first study drug administration. 10. Any abnormal vital signs, after no less than 5 minutes rest (supine position), as defined in the list below, at screening and/or prior to the first study drug administration. Out of range test may be repeated once for each visit at the discretion of the Investigator. 1. Systolic Blood Pressure (BP) \< 90 mmHg or \> 140 mmHg 2. Diastolic BP \< 50 mmHg or \> 90 mmHg 3. Heart Rate (HR) \< 45 or \> 90 beats per minute (bpm) 11. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG, which in the Investigator's opinion, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol-defined primary lead, or left ventricular hypertrophy at screening or prior to the first study drug administration (out of range test may be repeated once for each visit at the discretion of the Investigator). 12. Prolonged QT interval corrected for HR using Fridericia's formula (QTcF) \> 450 ms at screening or prior to first study drug administration. 13. Shortened QTcF \< 340 ms at screening or prior to first study drug administration. 14. Family history of long QT syndrome. 15. ECG interval measured from the onset of the P wave to the onset of the QRS complex (PR \[PQ\]) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular preexcitation) at screening or prior to first study drug administration. 16. PR (PQ) interval prolongation (\> 220 ms), persistent or intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation at screening or prior to first study drug administration. 17. Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with ECG interval measured from the onset of the QRS complex to the J point (QRS) \> 110 ms. Participants with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of ventricular hypertrophy or preexcitation at screening or prior to first study drug administration. 18. In the predose 24-hour telemetry, presence of ≥ 10 ventricular premature contractions (VPCs) during 1 hour, or ≥ 100 VPCs during 24 hours of telemetry, or any occurrence of paired VPCs (ventricular couplets) or other repetitive ventricular rhythms, including non-sustained or sustained (\> 30 second duration), slow (\< 100 bpm), or fast (≥ 100 bpm) ventricular tachycardias. 19. Any clinically significant illness in the 28 days prior to the first study drug administration. 20. Heavy smoker (\> 20 cigarettes per day) and/or is unable to abstain from smoking or unable to abstain from the use of prohibited nicotine containing products for at least 1 hour before and at least 6 hours after study drug administration (including e-cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, nicotine gum, or nicotine lozenges). 21. Regularly consumes excessive amounts of caffeine or xanthines within 30 days prior to screening, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day. 22. History of suicidal ideation within 1 year of screening (score of 4 or 5 as per the C-SSRS) or any suicidal behavior (as per C-SSRS) within 2 years of screening, or is currently at risk of suicide in the opinion of an Investigator. 23. Positive test result for alcohol and/or drugs of abuse upon admission on Day -1. Participants with positive marijuana results at admission may be rescheduled at the discretion of an Investigator. If Tetrahydrocannabinol is positive at admission, a cannabis intoxication evaluation will be done by an Investigator and participants may be permitted to continue in the study at the discretion of an Investigator. Other positive test results should be reviewed to determine if the participant may be rescheduled, in the opinion of an Investigator. 24. Positive test results for Human Immunodeficiency Virus (HIV)-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Virus Antibody (HCVAb). 25. Any other clinically significant abnormalities in laboratory test results at screening that would, in the opinion of an Investigator, increase the participant's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data. 26. Treatment with an investigational drug within 30 days or 5 times the half-life (whichever is longer) prior to screening. 27. Use of any prescription drugs (with the exception of hormone replacement therapy) in the 14 days prior to the first study drug administration, that in the opinion of an Investigator would put into question the status of the participant as healthy. 28. Use of St. John's wort in the 28 days prior to the first study drug administration. 29. Use of over-the-counter (OTC) products (including herbal preparations and supplements) within 7 days prior to the first study drug administration, with the exception of ibuprofen or acetaminophen. 30. Donation of plasma in the 7 days prior to the first study drug administration. 31. Donation of 1 unit of blood to American Red Cross or equivalent organization or donation of over 500 mL of blood in the 56 days prior to the first study drug administration. 32. Is, in the opinion of an Investigator or designee, considered unsuitable or unlikely to comply with the Study Protocol for any reason. 33. Poor venous access at screening, as judged by an Investigator. 34. Use of any prescribed or nonprescribed oral and topical inhibitors/inducers of CYP3A4 (including shampoo). 35. Is an AstraZeneca or study site employee or their close relatives.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1 | Day 1 | ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM\^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM\^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in EtCO2 is defined as an increase of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg on Day 1 are reported. |
| Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 15 | Day 15 | ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM\^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM\^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in end tidal carbon dioxide (EtCO2) is defined as an increase of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg on Day 15 are reported. |
| Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 1 | Day 1 | A reduction in SpO2 is defined as a reduction from baseline to \< 92% (sustained for at least 30 seconds). Number of participants with reduction in SpO2 to \< 92% on Day 1 are reported. |
| Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 15 | Day 15 | A reduction in SpO2 is defined as a reduction from baseline to \< 92% (sustained for at least 30 seconds). Number of participants with reduction in SpO2 to \< 92% on Day 15 are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg | Day 1 and Day 15 | Mean time to each increased EtCO2 episode of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) is reported. |
| Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg | Day 1 and Day 15 | Mean duration of each increased EtCO2 episode of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) is reported. |
| Post-dose Increase in EtCO2 Adjusted for Baseline | Day 1, Day 8, and Day 15 | Maximum post-dose increase in EtCO2 adjusted for baseline is reported. |
| Post-dose EtCO2 | Day 15 | Mean post-dose EtCO2 is reported. |
| Number of Participants With Reduced Respiratory Rate (RR) of < 6 Breaths/Min | Day 1, Day 8, and Day 15 | Number of participants with RR of \< 6 breaths/min (sustained for at least 30 seconds) are reported. |
| Time to Each Reduced Respiratory Rate Episode of < 6 Breaths/Min | Day 1, Day 8, and Day 15 | Mean time to each reduced respiratory rate episode of \< 6 breaths/min (sustained for at least 30 seconds) is reported. |
| Duration of Each Reduced Respiratory Rate Episode of < 6 Breaths/Min | Day 1, Day 8, and Day 15 | Mean duration of each reduced respiratory rate episode of \< 6 breaths/min (sustained for at least 30 seconds) is reported. |
| Post-dose Decrease in RR Adjusted for Baseline | Day 1, Day 8, and Day 15 | Maximum post-dose decrease in RR adjusted for baseline is reported. |
| Post-dose RR | Day 15 | Mean post-dose RR is reported. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Day 1 through end of study (Day 24) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. |
| Number of TEAEs | Day 1 through end of study (Day 24) | The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, Number of TEAEs are reported. |
| Number of TEAEs by Severity | Day 1 through end of study (Day 24) | The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, number of TEAEs by severity (mild, moderate, or severe) are reported. |
| Number of TEAEs by Relationship | Day 1 through end of study (Day 24) | The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, number of TEAEs by relationship (related or unrelated to the study drug) are reported. |
| Number of Participants With Clinically Significant Abnormal Vital Signs | Screening (Day -30 to -3) through Day 24 (end of study) | Number of participants with clinically significant abnormal vital signs are reported. Abnormal clinical vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, heart rate, and oral temperature). |
| Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs) | Screening (Day -30 to -3) through end of study (Day 24) | Number of participants with clinically significant abnormal ECGs are reported. Abnormal clinical ECG parameters are defined as any abnormal finding during analysis of 12-lead safety ECGs, 12-lead digital ECGs, and ECG telemetry. |
| Number of Participants With Clinically Significant Abnormal Laboratory Values | Screening (Day -30 to Day -3) through end of study (Day 24) | Number of participants with clinically significant abnormal laboratory values are reported. Abnormal clinical laboratory parameters are defined as any abnormal finding during analysis of hematology, clinical chemistry, coagulation, and urinalysis. |
| Number of Participants With Clinically Significant Abnormal Physical Examination Findings | Screening (Day -30 to Day -3) through end of study (Day 24) | Number of participants with clinically significant abnormal physical examination findings are reported. The physical examination included a general review of the following body systems (at minimum): head and neck, cardiovascular, respiratory, gastrointestinal, brief neurological and general appearance, unless a symptom oriented physical exam is indicated. |
| Number of Participants With Clinically Significant Neurological Examinations Findings | Screening (Day -30 to Day -3) through end of study (Day 24) | Number of participants with clinically significant neurological examinations findings are reported. Neurological examinations included assessments of basic mental status, cranial nerves, motor function, reflexes, sensation, proprioception, coordination, and gait. |
| Maximum Observed Concentration at Steady-state (Cmax,ss) of AZD4041 | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | The Cmax,ss of AZD4041 are reported. |
| Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments | Screening (Day -30 to Day -3) through end of study (Day 24) | The C-SSRS is a suicidal ideation and behavior rating scale with yes/no responses. Items 1-5 rates an individual's degree of suicidal ideation on a 0 (wish to be dead) to 5 (active suicidal ideation with specific plan and intent and behaviors) scale. C-SSRS outcomes are categories and have binary responses (yes/no). Suicidal ideation is considered when the participant responds a 'yes' to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS at any time during treatment. Items 6-10 of C-SSRS rates suicidal behavior where outcome is a simple yes/no response. Suicidal behavior was considered if participant answers a 'yes' to any one of the five suicidal behavior questions (Categories 6-10) on C-SSRS at any time during treatment. Number of participants with suicidal behavior and ideation per C-SSRS assessments are reported. |
| Number of Participants With Type of Medical Intervention Used for Each Event of Significantly Increased EtCO2, Reduced SpO2, or RR | Screening (Day -30 to Day -3) through end of study (Day 24) | Number of participants with type of medical intervention used for each event of significantly increased EtCO2, reduced SpO2, or RR are reported. |
| Time to Reach Maximum Observed Concentration at Steady State (Tmax,ss) of AZD4041 | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | The tmax,ss of AZD4041 are reported. |
| Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | The Cmax of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported. |
| Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | The Tmax of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported. |
| Area Under Plasma Concentration-time Curve Over a Dosing Interval (AUCτ) of AZD4041 | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | The AUCτ of AZD4041 are reported. |
| Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | The AUC0-t of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported. |
| Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | The (AUC0-∞) of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported. |
| Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | The t1/2λz of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported. |
| Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | The tlast of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported. |
| Total Body Clearance (CL) of Morphine | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | The CL of morphine are reported. |
| Volume of Distribution Based on the Terminal Phase (Vz) of Morphine | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | The Vz of morphine are reported. |
| Terminal Elimination Half-life (t1/2λz) of AZD4041 | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | The t1/2λz of AZD4041 are reported. |
| Average Concentration Over a Dosing Interval (Cav) of AZD4041 | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | The Cav of AZD4041 are reported. |
| Apparent Total Body Clearance at Steady State (CLss/F) of AZD4041 | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | The CLss/F of AZD4041 are reported. |
| Apparent Volume of Distribution at Steady State Based on the Terminal Phase (Vzss/F) of AZD4041 | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | The Vzss/F of AZD4041 are reported |
| Observed Lowest Concentration Before the Next Dose is Administered at Steady State (Ctrough,ss) of AZD4041 | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | The Ctrough,ss of AZD4041 are reported. |
| Amount of AZD4041 Excreted Unchanged in Urine (Aeτ) | Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose | The Aeτ of AZD4041 is reported. |
| Apparent Fraction of AZD4041 Excreted Unchanged in Urine (Feτ/F) | Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose | The Feτ/F of AZD4041 is reported. |
| Renal Clearance (CLR) of AZD4041 | Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose | The CLR of AZD4041 is reported. |
| Terminal Elimination Half-life (t1/2) of AZD4041 | Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose | The t1/2 of AZD4041 is reported. |
| Plasma Concentration of Morphine Over Time | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose | Plasma concentration of morphine over time was reported. |
| Time to Reduction in SpO2 to < 92% | Day 1 and Day 15 | Mean time to reduction from baseline in SpO2 to \< 92% (sustained for at least 30 seconds) is reported. |
| Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | Plasma concentration of morphine-6-glucuronide over time are reported. |
| Plasma Concentration of AZD4041 Over Time | Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose, and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose | Plasma concentration of AZD4041 over time are reported. |
| Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites | Plasma concentration of morphine-3-glucuronide over time are reported. |
| Duration of Reduction in SpO2 to < 92% | Day 1 and Day 15 | Mean duration of reduction from baseline in SpO2 to \< 92% (sustained for at least 30 seconds) is reported. |
| Post-dose Reduction of SpO2 Adjusted for Baseline | Day 1, Day 8, and Day 15 | Maximum post-dose reduction of SpO2 adjusted for baseline is reported. |
| Post-dose SpO2 | Day 15 | Mean post-dose SpO2 is reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1. | 26 |
| Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1. | 15 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Non-compliance with study procedures | 0 | 1 |
| Overall Study | Not treated | 3 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Morphine Then Placebo Then Morphine + Placebo | Total | Morphine Then AZD4041 Then Morphine + AZD4041 |
|---|---|---|---|
| Age, Continuous | 34.8 Years STANDARD_DEVIATION 5.75 | 33.8 Years STANDARD_DEVIATION 6.39 | 33.2 Years STANDARD_DEVIATION 6.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 38 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 31 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 10 Participants | 7 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 14 Participants | 37 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 15 |
| other Total, other adverse events | 26 / 26 | 14 / 15 |
| serious Total, serious adverse events | 0 / 26 | 0 / 15 |
Outcome results
Primary
Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1
ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM\^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM\^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in EtCO2 is defined as an increase of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg on Day 1 are reported.
Time frame: Day 1
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1 | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1 | 0 Participants |
Primary
Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 15
ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM\^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM\^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in end tidal carbon dioxide (EtCO2) is defined as an increase of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg on Day 15 are reported.
Time frame: Day 15
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 15 | 2 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 15 | 1 Participants |
Primary
Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 1
A reduction in SpO2 is defined as a reduction from baseline to \< 92% (sustained for at least 30 seconds). Number of participants with reduction in SpO2 to \< 92% on Day 1 are reported.
Time frame: Day 1
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 1 | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 1 | 0 Participants |
Primary
Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 15
A reduction in SpO2 is defined as a reduction from baseline to \< 92% (sustained for at least 30 seconds). Number of participants with reduction in SpO2 to \< 92% on Day 15 are reported.
Time frame: Day 15
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 15 | 1 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 15 | 0 Participants |
Secondary
Amount of AZD4041 Excreted Unchanged in Urine (Aeτ)
The Aeτ of AZD4041 is reported.
Time frame: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041 and who were evaluable at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Amount of AZD4041 Excreted Unchanged in Urine (Aeτ) | 390400 ng | Geometric Coefficient of Variation 63.03 |
Secondary
Apparent Fraction of AZD4041 Excreted Unchanged in Urine (Feτ/F)
The Feτ/F of AZD4041 is reported.
Time frame: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041 and who were evaluable at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Apparent Fraction of AZD4041 Excreted Unchanged in Urine (Feτ/F) | 1.562 Percentage | Geometric Coefficient of Variation 63.03 |
Secondary
Apparent Total Body Clearance at Steady State (CLss/F) of AZD4041
The CLss/F of AZD4041 are reported.
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Apparent Total Body Clearance at Steady State (CLss/F) of AZD4041 | Day 8 | 3.514 L/h | Geometric Coefficient of Variation 31.15 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Apparent Total Body Clearance at Steady State (CLss/F) of AZD4041 | Day 15 | 3.242 L/h | Geometric Coefficient of Variation 28.34 |
Secondary
Apparent Volume of Distribution at Steady State Based on the Terminal Phase (Vzss/F) of AZD4041
The Vzss/F of AZD4041 are reported
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Apparent Volume of Distribution at Steady State Based on the Terminal Phase (Vzss/F) of AZD4041 | Day 8 | 73.19 Liter | Geometric Coefficient of Variation 57.65 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Apparent Volume of Distribution at Steady State Based on the Terminal Phase (Vzss/F) of AZD4041 | Day 15 | 56.79 Liter | Geometric Coefficient of Variation 37.29 |
Secondary
Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites
The (AUC0-∞) of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine (Day 1) | 140.5 h*ng/mL | Geometric Coefficient of Variation 26.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine (Day 15) | 142.6 h*ng/mL | Geometric Coefficient of Variation 28.33 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 2259 h*ng/mL | Geometric Coefficient of Variation 20.29 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 2284 h*ng/mL | Geometric Coefficient of Variation 17.84 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 372.6 h*ng/mL | Geometric Coefficient of Variation 48.69 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 371.2 h*ng/mL | Geometric Coefficient of Variation 16.37 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 389.4 h*ng/mL | Geometric Coefficient of Variation 17.13 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine (Day 1) | 133.8 h*ng/mL | Geometric Coefficient of Variation 21.19 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 2363 h*ng/mL | Geometric Coefficient of Variation 15.32 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine (Day 15) | 140.8 h*ng/mL | Geometric Coefficient of Variation 17.87 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 408.3 h*ng/mL | Geometric Coefficient of Variation 19.38 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 2404 h*ng/mL | Geometric Coefficient of Variation 17.43 |
Secondary
Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites
The AUC0-t of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine (Day 1) | 132.5 h*ng/mL | Geometric Coefficient of Variation 26.78 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine (Day 15) | 135.5 h*ng/mL | Geometric Coefficient of Variation 29.08 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 1996 h*ng/mL | Geometric Coefficient of Variation 18.55 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 2120 h*ng/mL | Geometric Coefficient of Variation 19.43 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 315.3 h*ng/mL | Geometric Coefficient of Variation 17.76 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 342.7 h*ng/mL | Geometric Coefficient of Variation 16.45 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 342.0 h*ng/mL | Geometric Coefficient of Variation 18.68 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine (Day 1) | 124.5 h*ng/mL | Geometric Coefficient of Variation 23.59 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 2194 h*ng/mL | Geometric Coefficient of Variation 15.11 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine (Day 15) | 128.2 h*ng/mL | Geometric Coefficient of Variation 17.33 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 380.3 h*ng/mL | Geometric Coefficient of Variation 18.66 |
| Morphine Then Placebo Then Morphine + Placebo | Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 2067 h*ng/mL | Geometric Coefficient of Variation 15.21 |
Secondary
Area Under Plasma Concentration-time Curve Over a Dosing Interval (AUCτ) of AZD4041
The AUCτ of AZD4041 are reported.
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve Over a Dosing Interval (AUCτ) of AZD4041 | Day 8 | 7114 h*ng/mL | Geometric Coefficient of Variation 31.15 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Area Under Plasma Concentration-time Curve Over a Dosing Interval (AUCτ) of AZD4041 | Day 15 | 7711 h*ng/mL | Geometric Coefficient of Variation 28.34 |
Secondary
Average Concentration Over a Dosing Interval (Cav) of AZD4041
The Cav of AZD4041 are reported.
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Average Concentration Over a Dosing Interval (Cav) of AZD4041 | Day 8 | 296.4 ng/mL | Geometric Coefficient of Variation 31.15 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Average Concentration Over a Dosing Interval (Cav) of AZD4041 | Day 15 | 321.3 ng/mL | Geometric Coefficient of Variation 28.34 |
Secondary
Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg
Mean duration of each increased EtCO2 episode of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) is reported.
Time frame: Day 1 and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes those participants who had EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). On Day 1, number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) was 0.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg | Day 15 | 8.202 Minutes | Standard Deviation 6.8859 |
| Morphine Then Placebo Then Morphine + Placebo | Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg | Day 15 | 0.750 Minutes | — |
| Unknown | Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg | Day 1 | — Minutes | — |
Secondary
Duration of Each Reduced Respiratory Rate Episode of < 6 Breaths/Min
Mean duration of each reduced respiratory rate episode of \< 6 breaths/min (sustained for at least 30 seconds) is reported.
Time frame: Day 1, Day 8, and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants with RR of \< 6 breaths/min (sustained for at least 30 seconds) was 0.
Secondary
Duration of Reduction in SpO2 to < 92%
Mean duration of reduction from baseline in SpO2 to \< 92% (sustained for at least 30 seconds) is reported.
Time frame: Day 1 and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes only those participants who had reduction in SpO2 to \< 92% (sustained for at least 30 seconds). On Day 1, number of participants with reduction in SpO2 to \< 92% (sustained for at least 30 seconds) was 0.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Duration of Reduction in SpO2 to < 92% | Day 15 | 1.083 Minutes |
| Unknown | Duration of Reduction in SpO2 to < 92% | Day 1 | — Minutes |
Secondary
Maximum Observed Concentration at Steady-state (Cmax,ss) of AZD4041
The Cmax,ss of AZD4041 are reported.
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Maximum Observed Concentration at Steady-state (Cmax,ss) of AZD4041 | Day 8 | 717.8 ng/mL | Geometric Coefficient of Variation 23.95 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Maximum Observed Concentration at Steady-state (Cmax,ss) of AZD4041 | Day 15 | 660.7 ng/mL | Geometric Coefficient of Variation 22.14 |
Secondary
Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites
The Cmax of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: Pharmacokinetic (PK) population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine (Day 1) | 96.24 ng/mL | Geometric Coefficient of Variation 22.07 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine (Day 15) | 88.32 ng/mL | Geometric Coefficient of Variation 24.14 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 313.7 ng/mL | Geometric Coefficient of Variation 25.54 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 291.0 ng/mL | Geometric Coefficient of Variation 23.34 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 56.40 ng/mL | Geometric Coefficient of Variation 21.46 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 53.54 ng/mL | Geometric Coefficient of Variation 19.06 |
| Morphine Then Placebo Then Morphine + Placebo | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 64.44 ng/mL | Geometric Coefficient of Variation 10.6 |
| Morphine Then Placebo Then Morphine + Placebo | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine (Day 1) | 95.51 ng/mL | Geometric Coefficient of Variation 16.95 |
| Morphine Then Placebo Then Morphine + Placebo | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 300.8 ng/mL | Geometric Coefficient of Variation 10.58 |
| Morphine Then Placebo Then Morphine + Placebo | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine (Day 15) | 88.54 ng/mL | Geometric Coefficient of Variation 20.74 |
| Morphine Then Placebo Then Morphine + Placebo | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 59.88 ng/mL | Geometric Coefficient of Variation 12.96 |
| Morphine Then Placebo Then Morphine + Placebo | Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 352.9 ng/mL | Geometric Coefficient of Variation 14.03 |
Secondary
Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs)
Number of participants with clinically significant abnormal ECGs are reported. Abnormal clinical ECG parameters are defined as any abnormal finding during analysis of 12-lead safety ECGs, 12-lead digital ECGs, and ECG telemetry.
Time frame: Screening (Day -30 to -3) through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs) | 2 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs) | 1 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Laboratory Values
Number of participants with clinically significant abnormal laboratory values are reported. Abnormal clinical laboratory parameters are defined as any abnormal finding during analysis of hematology, clinical chemistry, coagulation, and urinalysis.
Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Physical Examination Findings
Number of participants with clinically significant abnormal physical examination findings are reported. The physical examination included a general review of the following body systems (at minimum): head and neck, cardiovascular, respiratory, gastrointestinal, brief neurological and general appearance, unless a symptom oriented physical exam is indicated.
Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Clinically Significant Abnormal Physical Examination Findings | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Clinically Significant Abnormal Physical Examination Findings | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Vital Signs
Number of participants with clinically significant abnormal vital signs are reported. Abnormal clinical vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, heart rate, and oral temperature).
Time frame: Screening (Day -30 to -3) through Day 24 (end of study)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Clinically Significant Abnormal Vital Signs | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Clinically Significant Abnormal Vital Signs | 0 Participants |
Secondary
Number of Participants With Clinically Significant Neurological Examinations Findings
Number of participants with clinically significant neurological examinations findings are reported. Neurological examinations included assessments of basic mental status, cranial nerves, motor function, reflexes, sensation, proprioception, coordination, and gait.
Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Clinically Significant Neurological Examinations Findings | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Clinically Significant Neurological Examinations Findings | 0 Participants |
Secondary
Number of Participants With Reduced Respiratory Rate (RR) of < 6 Breaths/Min
Number of participants with RR of \< 6 breaths/min (sustained for at least 30 seconds) are reported.
Time frame: Day 1, Day 8, and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Reduced Respiratory Rate (RR) of < 6 Breaths/Min | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Reduced Respiratory Rate (RR) of < 6 Breaths/Min | 0 Participants |
Secondary
Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments
The C-SSRS is a suicidal ideation and behavior rating scale with yes/no responses. Items 1-5 rates an individual's degree of suicidal ideation on a 0 (wish to be dead) to 5 (active suicidal ideation with specific plan and intent and behaviors) scale. C-SSRS outcomes are categories and have binary responses (yes/no). Suicidal ideation is considered when the participant responds a 'yes' to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS at any time during treatment. Items 6-10 of C-SSRS rates suicidal behavior where outcome is a simple yes/no response. Suicidal behavior was considered if participant answers a 'yes' to any one of the five suicidal behavior questions (Categories 6-10) on C-SSRS at any time during treatment. Number of participants with suicidal behavior and ideation per C-SSRS assessments are reported.
Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments | Suicidal Ideation | 0 Participants |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments | Suicidal Behaviours | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments | Suicidal Ideation | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments | Suicidal Behaviours | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Time frame: Day 1 through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 26 Participants |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 14 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 0 Participants |
Secondary
Number of Participants With Type of Medical Intervention Used for Each Event of Significantly Increased EtCO2, Reduced SpO2, or RR
Number of participants with type of medical intervention used for each event of significantly increased EtCO2, reduced SpO2, or RR are reported.
Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of Participants With Type of Medical Intervention Used for Each Event of Significantly Increased EtCO2, Reduced SpO2, or RR | 0 Participants |
| Morphine Then Placebo Then Morphine + Placebo | Number of Participants With Type of Medical Intervention Used for Each Event of Significantly Increased EtCO2, Reduced SpO2, or RR | 0 Participants |
Secondary
Number of TEAEs
The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, Number of TEAEs are reported.
Time frame: Day 1 through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of TEAEs | 134 Events |
| Morphine Then Placebo Then Morphine + Placebo | Number of TEAEs | 102 Events |
Secondary
Number of TEAEs by Relationship
The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, number of TEAEs by relationship (related or unrelated to the study drug) are reported.
Time frame: Day 1 through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of TEAEs by Relationship | Related | 125 Events |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of TEAEs by Relationship | Unrelated | 9 Events |
| Morphine Then Placebo Then Morphine + Placebo | Number of TEAEs by Relationship | Unrelated | 8 Events |
| Morphine Then Placebo Then Morphine + Placebo | Number of TEAEs by Relationship | Related | 94 Events |
Secondary
Number of TEAEs by Severity
The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, number of TEAEs by severity (mild, moderate, or severe) are reported.
Time frame: Day 1 through end of study (Day 24)
Population: The safety population included all participants who received at least 1 dose of morphine.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of TEAEs by Severity | Mild | 129 Events |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of TEAEs by Severity | Moderate | 5 Events |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Number of TEAEs by Severity | Severe | 0 Events |
| Morphine Then Placebo Then Morphine + Placebo | Number of TEAEs by Severity | Mild | 99 Events |
| Morphine Then Placebo Then Morphine + Placebo | Number of TEAEs by Severity | Moderate | 3 Events |
| Morphine Then Placebo Then Morphine + Placebo | Number of TEAEs by Severity | Severe | 0 Events |
Secondary
Observed Lowest Concentration Before the Next Dose is Administered at Steady State (Ctrough,ss) of AZD4041
The Ctrough,ss of AZD4041 are reported.
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Observed Lowest Concentration Before the Next Dose is Administered at Steady State (Ctrough,ss) of AZD4041 | Day 8 | 133.8 ng/mL | Geometric Coefficient of Variation 66.35 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Observed Lowest Concentration Before the Next Dose is Administered at Steady State (Ctrough,ss) of AZD4041 | Day 15 | 149.5 ng/mL | Geometric Coefficient of Variation 67.1 |
Secondary
Plasma Concentration of AZD4041 Over Time
Plasma concentration of AZD4041 over time are reported.
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose, and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (3 hours) | 531.67 ng/mL | Geometric Coefficient of Variation 29.9 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (4 hours) | 508.05 ng/mL | Geometric Coefficient of Variation 30.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (6 hours) | 353.26 ng/mL | Geometric Coefficient of Variation 33.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (4 hours) | 524.01 ng/mL | Geometric Coefficient of Variation 34.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (predose) | 133.83 ng/mL | Geometric Coefficient of Variation 66.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (0.08 hours) | 186.27 ng/mL | Geometric Coefficient of Variation 47.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (0.25 hours) | 435.07 ng/mL | Geometric Coefficient of Variation 44.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (0.5 hours) | 690.91 ng/mL | Geometric Coefficient of Variation 28.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (1 hours) | 623.75 ng/mL | Geometric Coefficient of Variation 28.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (1.5 hours) | 602.16 ng/mL | Geometric Coefficient of Variation 32.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (2 hours) | 576.78 ng/mL | Geometric Coefficient of Variation 25.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (8 hours) | 327.88 ng/mL | Geometric Coefficient of Variation 34.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (12 hours) | 227.32 ng/mL | Geometric Coefficient of Variation 41.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 8 (24 hours) | 136.56 ng/mL | Geometric Coefficient of Variation 57.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (predose) | 149.54 ng/mL | Geometric Coefficient of Variation 67.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (0.08 hours) | 192.53 ng/mL | Geometric Coefficient of Variation 53.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (0.25 hours) | 369.16 ng/mL | Geometric Coefficient of Variation 52.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (0.5 hours) | 467.16 ng/mL | Geometric Coefficient of Variation 45.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (1 hours) | 504.23 ng/mL | Geometric Coefficient of Variation 33.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (1.5 hours) | 546.10 ng/mL | Geometric Coefficient of Variation 35 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (2 hours) | 523.23 ng/mL | Geometric Coefficient of Variation 33.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (3 hours) | 566.76 ng/mL | Geometric Coefficient of Variation 23.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (6 hours) | 432.55 ng/mL | Geometric Coefficient of Variation 29.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (8 hours) | 380.48 ng/mL | Geometric Coefficient of Variation 33.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (12 hours) | 264.56 ng/mL | Geometric Coefficient of Variation 39.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (24 hours) | 157.21 ng/mL | Geometric Coefficient of Variation 53.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (36 hours) | 54.33 ng/mL | Geometric Coefficient of Variation 94.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (48 hours) | 33.77 ng/mL | Geometric Coefficient of Variation 133.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of AZD4041 Over Time | Day 15 (72 hours) | 7.97 ng/mL | Geometric Coefficient of Variation 240 |
Secondary
Plasma Concentration of Morphine-3-glucuronide Over Time
Plasma concentration of morphine-3-glucuronide over time are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (2 hours) | 222.77 ng/mL | Geometric Coefficient of Variation 20.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (0.08 hours) | 235.04 ng/mL | Geometric Coefficient of Variation 42.8 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (24 hours) | 23.17 ng/mL | Geometric Coefficient of Variation 32.8 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (0.25 hours) | 262.41 ng/mL | Geometric Coefficient of Variation 34.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (3 hours) | 179.81 ng/mL | Geometric Coefficient of Variation 24 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (0.5 hours) | 263.96 ng/mL | Geometric Coefficient of Variation 34.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (0.5 hours) | 282.31 ng/mL | Geometric Coefficient of Variation 27.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (1 hours) | 254.13 ng/mL | Geometric Coefficient of Variation 21.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (4 hours) | 146.71 ng/mL | Geometric Coefficient of Variation 24.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (1.5 hours) | 234.80 ng/mL | Geometric Coefficient of Variation 19.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (0.08 hours) | 261.17 ng/mL | Geometric Coefficient of Variation 42.9 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (2 hours) | 213.71 ng/mL | Geometric Coefficient of Variation 19.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (6 hours) | 97.80 ng/mL | Geometric Coefficient of Variation 24.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (3 hours) | 176.05 ng/mL | Geometric Coefficient of Variation 22.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (1 hours) | 257.89 ng/mL | Geometric Coefficient of Variation 27.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (4 hours) | 144.41 ng/mL | Geometric Coefficient of Variation 24.8 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (8 hours) | 65.29 ng/mL | Geometric Coefficient of Variation 23.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (6 hours) | 91.78 ng/mL | Geometric Coefficient of Variation 41.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (predose) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (8 hours) | 62.28 ng/mL | Geometric Coefficient of Variation 28.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (1.5 hours) | 244.91 ng/mL | Geometric Coefficient of Variation 22.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (12 hours) | 39.26 ng/mL | Geometric Coefficient of Variation 34.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (36 hours) | 12.53 ng/mL | Geometric Coefficient of Variation 48.8 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (24 hours) | 24.87 ng/mL | Geometric Coefficient of Variation 31.9 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (0.25 hours) | 287.69 ng/mL | Geometric Coefficient of Variation 28.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (36 hours) | 11.78 ng/mL | Geometric Coefficient of Variation 53.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (predose) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (48 hours) | 6.76 ng/mL | Geometric Coefficient of Variation 38 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (12 hours) | 30.21 ng/mL | Geometric Coefficient of Variation 44.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (48 hours) | 8.40 ng/mL | Geometric Coefficient of Variation 30.5 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (12 hours) | 35.03 ng/mL | Geometric Coefficient of Variation 43 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (predose) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (0.08 hours) | 330.85 ng/mL | Geometric Coefficient of Variation 16.9 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (0.25 hours) | 336.02 ng/mL | Geometric Coefficient of Variation 12.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (0.5 hours) | 311.44 ng/mL | Geometric Coefficient of Variation 10.9 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (1 hours) | 276.48 ng/mL | Geometric Coefficient of Variation 14.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (1.5 hours) | 247.20 ng/mL | Geometric Coefficient of Variation 15.5 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (2 hours) | 215.93 ng/mL | Geometric Coefficient of Variation 18.5 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (3 hours) | 163.04 ng/mL | Geometric Coefficient of Variation 39.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (4 hours) | 146.83 ng/mL | Geometric Coefficient of Variation 19 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (6 hours) | 92.21 ng/mL | Geometric Coefficient of Variation 21.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (8 hours) | 57.07 ng/mL | Geometric Coefficient of Variation 30.3 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (24 hours) | 27.71 ng/mL | Geometric Coefficient of Variation 32.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 1 (36 hours) | 14.19 ng/mL | Geometric Coefficient of Variation 39.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (predose) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (0.08 hours) | 255.36 ng/mL | Geometric Coefficient of Variation 31.2 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (0.25 hours) | 289.85 ng/mL | Geometric Coefficient of Variation 14.2 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (0.5 hours) | 278.58 ng/mL | Geometric Coefficient of Variation 16.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (1 hours) | 264.39 ng/mL | Geometric Coefficient of Variation 11.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (1.5 hours) | 243.99 ng/mL | Geometric Coefficient of Variation 13.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (2 hours) | 218.39 ng/mL | Geometric Coefficient of Variation 14.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (3 hours) | 179.70 ng/mL | Geometric Coefficient of Variation 16 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (4 hours) | 145.37 ng/mL | Geometric Coefficient of Variation 19.5 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (6 hours) | 91.87 ng/mL | Geometric Coefficient of Variation 15.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (8 hours) | 59.38 ng/mL | Geometric Coefficient of Variation 21.4 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (12 hours) | 30.01 ng/mL | Geometric Coefficient of Variation 47.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (24 hours) | 27.49 ng/mL | Geometric Coefficient of Variation 24.3 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-3-glucuronide Over Time | Day 15 (36 hours) | 16.90 ng/mL | Geometric Coefficient of Variation 26.2 |
Secondary
Plasma Concentration of Morphine-6-glucuronide Over Time
Plasma concentration of morphine-6-glucuronide over time are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (predose) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (0.08 hours) | 22.52 ng/mL | Geometric Coefficient of Variation 53 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (0.25 hours) | 42.25 ng/mL | Geometric Coefficient of Variation 35.8 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (0.5 hours) | 51.95 ng/mL | Geometric Coefficient of Variation 27.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (1 hours) | 51.22 ng/mL | Geometric Coefficient of Variation 24.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (1.5 hours) | 46.95 ng/mL | Geometric Coefficient of Variation 17.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (2 hours) | 41.86 ng/mL | Geometric Coefficient of Variation 16 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (3 hours) | 31.64 ng/mL | Geometric Coefficient of Variation 18.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (4 hours) | 23.97 ng/mL | Geometric Coefficient of Variation 20.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (6 hours) | 14.95 ng/mL | Geometric Coefficient of Variation 23.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (8 hours) | 9.05 ng/mL | Geometric Coefficient of Variation 22.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (12 hours) | 3.83 ng/mL | Geometric Coefficient of Variation 41.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (24 hours) | 3.45 ng/mL | Geometric Coefficient of Variation 43.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (36 hours) | 1.76 ng/mL | Geometric Coefficient of Variation 45.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (predose) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (0.08 hours) | 20.40 ng/mL | Geometric Coefficient of Variation 55.9 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (0.25 hours) | 37.25 ng/mL | Geometric Coefficient of Variation 43.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (0.5 hours) | 48.42 ng/mL | Geometric Coefficient of Variation 34.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (1 hours) | 51.86 ng/mL | Geometric Coefficient of Variation 18.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (1.5 hours) | 47.25 ng/mL | Geometric Coefficient of Variation 15.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (2 hours) | 41.51 ng/mL | Geometric Coefficient of Variation 16.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (3 hours) | 32.10 ng/mL | Geometric Coefficient of Variation 14.8 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (4 hours) | 25.57 ng/mL | Geometric Coefficient of Variation 15.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (6 hours) | 14.39 ng/mL | Geometric Coefficient of Variation 34.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (8 hours) | 8.93 ng/mL | Geometric Coefficient of Variation 23.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (12 hours) | 5.57 ng/mL | Geometric Coefficient of Variation 37 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (24 hours) | 3.84 ng/mL | Geometric Coefficient of Variation 34.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (36 hours) | 1.73 ng/mL | Geometric Coefficient of Variation 47.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (48 hours) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (predose) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (predose) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (12 hours) | 4.39 ng/mL | Geometric Coefficient of Variation 54.5 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (0.08 hours) | 32.79 ng/mL | Geometric Coefficient of Variation 23.4 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (0.08 hours) | 23.45 ng/mL | Geometric Coefficient of Variation 44.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (0.25 hours) | 56.30 ng/mL | Geometric Coefficient of Variation 17.1 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (4 hours) | 26.76 ng/mL | Geometric Coefficient of Variation 19 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (0.5 hours) | 62.02 ng/mL | Geometric Coefficient of Variation 8.9 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (0.25 hours) | 46.21 ng/mL | Geometric Coefficient of Variation 21.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (1 hours) | 57.49 ng/mL | Geometric Coefficient of Variation 16.2 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (36 hours) | 2.51 ng/mL | Geometric Coefficient of Variation 27 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (1.5 hours) | 50.15 ng/mL | Geometric Coefficient of Variation 13.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (0.5 hours) | 56.18 ng/mL | Geometric Coefficient of Variation 19.4 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (2 hours) | 42.36 ng/mL | Geometric Coefficient of Variation 22.5 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (6 hours) | 15.20 ng/mL | Geometric Coefficient of Variation 20.3 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (3 hours) | 29.23 ng/mL | Geometric Coefficient of Variation 37.9 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (1 hours) | 57.32 ng/mL | Geometric Coefficient of Variation 13 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (4 hours) | 25.24 ng/mL | Geometric Coefficient of Variation 20.2 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (24 hours) | 4.43 ng/mL | Geometric Coefficient of Variation 32.2 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (6 hours) | 14.55 ng/mL | Geometric Coefficient of Variation 24 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (1.5 hours) | 52.46 ng/mL | Geometric Coefficient of Variation 14.1 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (8 hours) | 8.32 ng/mL | Geometric Coefficient of Variation 32.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (8 hours) | 9.15 ng/mL | Geometric Coefficient of Variation 25.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (12 hours) | 4.88 ng/mL | Geometric Coefficient of Variation 46.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (2 hours) | 46.16 ng/mL | Geometric Coefficient of Variation 15.5 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (24 hours) | 4.30 ng/mL | Geometric Coefficient of Variation 37.1 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (48 hours) | 1.34 ng/mL | Geometric Coefficient of Variation 33.5 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 1 (36 hours) | 1.91 ng/mL | Geometric Coefficient of Variation 40.9 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine-6-glucuronide Over Time | Day 15 (3 hours) | 34.90 ng/mL | Geometric Coefficient of Variation 17.5 |
Secondary
Plasma Concentration of Morphine Over Time
Plasma concentration of morphine over time was reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (predose) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (Predose) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (0.08 hour) | 88.32 ng/mL | Geometric Coefficient of Variation 24.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (4 hour) | 9.92 ng/mL | Geometric Coefficient of Variation 27.7 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (0.25 hour) | 56.83 ng/mL | Geometric Coefficient of Variation 24.9 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (1 hour) | 29.42 ng/mL | Geometric Coefficient of Variation 29.8 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (0.5 hour) | 39.88 ng/mL | Geometric Coefficient of Variation 29.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (6 hour) | 4.99 ng/mL | Geometric Coefficient of Variation 33.6 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (1 hour) | 30.09 ng/mL | Geometric Coefficient of Variation 33 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (0.25 hour) | 57.04 ng/mL | Geometric Coefficient of Variation 23.9 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (1.5 hour) | 24.31 ng/mL | Geometric Coefficient of Variation 28.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (8 hour) | 3.05 ng/mL | Geometric Coefficient of Variation 31.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (2 hour) | 20.54 ng/mL | Geometric Coefficient of Variation 31.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (1.5 hour) | 25.13 ng/mL | Geometric Coefficient of Variation 25.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (3 hour) | 14.16 ng/mL | Geometric Coefficient of Variation 29.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (12 hour) | 1.21 ng/mL | Geometric Coefficient of Variation 19.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (4 hour) | 10.74 ng/mL | Geometric Coefficient of Variation 33.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (0.08 hour) | 96.24 ng/mL | Geometric Coefficient of Variation 22.1 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (6 hour) | 5.06 ng/mL | Geometric Coefficient of Variation 41.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (24 hour) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (8 hour) | 2.85 ng/mL | Geometric Coefficient of Variation 34.4 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (0.5 hour) | 40.89 ng/mL | Geometric Coefficient of Variation 25.5 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (12 hour) | 1.42 ng/mL | Geometric Coefficient of Variation 30 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (36 hour) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (24 hour) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (3 hour) | 14.00 ng/mL | Geometric Coefficient of Variation 24.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 15 (36 hour) | NA ng/mL | — |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Plasma Concentration of Morphine Over Time | Day 1 (2 hour) | 19.43 ng/mL | Geometric Coefficient of Variation 25 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (36 hour) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (Predose) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (0.08 hour) | 95.51 ng/mL | Geometric Coefficient of Variation 16.9 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (0.25 hour) | 54.16 ng/mL | Geometric Coefficient of Variation 20.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (0.5 hour) | 38.50 ng/mL | Geometric Coefficient of Variation 22.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (1 hour) | 26.58 ng/mL | Geometric Coefficient of Variation 22.9 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (1.5 hour) | 21.07 ng/mL | Geometric Coefficient of Variation 24.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (2 hour) | 17.24 ng/mL | Geometric Coefficient of Variation 27.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (3 hour) | 11.82 ng/mL | Geometric Coefficient of Variation 33.9 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (4 hour) | 9.50 ng/mL | Geometric Coefficient of Variation 30 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (6 hour) | 4.77 ng/mL | Geometric Coefficient of Variation 35.4 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (8 hour) | 2.99 ng/mL | Geometric Coefficient of Variation 33.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (12 hour) | 1.32 ng/mL | Geometric Coefficient of Variation 25.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (24 hour) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 1 (36 hour) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (predose) | NA ng/mL | — |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (0.08 hour) | 88.54 ng/mL | Geometric Coefficient of Variation 20.7 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (0.25 hour) | 53.14 ng/mL | Geometric Coefficient of Variation 22.4 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (0.5 hour) | 38.55 ng/mL | Geometric Coefficient of Variation 25 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (1 hour) | 27.00 ng/mL | Geometric Coefficient of Variation 22.1 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (1.5 hour) | 22.00 ng/mL | Geometric Coefficient of Variation 18 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (2 hour) | 18.09 ng/mL | Geometric Coefficient of Variation 21.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (3 hour) | 13.99 ng/mL | Geometric Coefficient of Variation 19.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (4 hour) | 10.00 ng/mL | Geometric Coefficient of Variation 23.6 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (6 hour) | 4.87 ng/mL | Geometric Coefficient of Variation 35.8 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (8 hour) | 2.93 ng/mL | Geometric Coefficient of Variation 34 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (12 hour) | 1.36 ng/mL | Geometric Coefficient of Variation 26.1 |
| Morphine Then Placebo Then Morphine + Placebo | Plasma Concentration of Morphine Over Time | Day 15 (24 hour) | NA ng/mL | — |
Secondary
Post-dose Decrease in RR Adjusted for Baseline
Maximum post-dose decrease in RR adjusted for baseline is reported.
Time frame: Day 1, Day 8, and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Decrease in RR Adjusted for Baseline | Day 1 | 4.852 Breaths/min | Standard Deviation 1.7684 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Decrease in RR Adjusted for Baseline | Day 8 | 4.133 Breaths/min | Standard Deviation 2.5477 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Decrease in RR Adjusted for Baseline | Day 15 | 5.133 Breaths/min | Standard Deviation 2.4346 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Decrease in RR Adjusted for Baseline | Day 1 | 5.523 Breaths/min | Standard Deviation 2.2649 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Decrease in RR Adjusted for Baseline | Day 8 | 4.667 Breaths/min | Standard Deviation 2.1252 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Decrease in RR Adjusted for Baseline | Day 15 | 6.116 Breaths/min | Standard Deviation 2.2576 |
Secondary
Post-dose EtCO2
Mean post-dose EtCO2 is reported.
Time frame: Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes the number of participants who were evaluable for the specified outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose EtCO2 | 41.870 mmHg | Standard Deviation 2.8188 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose EtCO2 | 40.923 mmHg | Standard Deviation 2.441 |
Secondary
Post-dose Increase in EtCO2 Adjusted for Baseline
Maximum post-dose increase in EtCO2 adjusted for baseline is reported.
Time frame: Day 1, Day 8, and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Increase in EtCO2 Adjusted for Baseline | Day 1 | 6.501 mmHg | Standard Deviation 1.9432 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Increase in EtCO2 Adjusted for Baseline | Day 8 | 3.141 mmHg | Standard Deviation 2.844 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Increase in EtCO2 Adjusted for Baseline | Day 15 | 7.261 mmHg | Standard Deviation 2.522 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Increase in EtCO2 Adjusted for Baseline | Day 1 | 7.177 mmHg | Standard Deviation 1.6955 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Increase in EtCO2 Adjusted for Baseline | Day 8 | 3.452 mmHg | Standard Deviation 2.1808 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Increase in EtCO2 Adjusted for Baseline | Day 15 | 7.462 mmHg | Standard Deviation 1.9624 |
Secondary
Post-dose Reduction of SpO2 Adjusted for Baseline
Maximum post-dose reduction of SpO2 adjusted for baseline is reported.
Time frame: Day 1, Day 8, and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Reduction of SpO2 Adjusted for Baseline | Day 1 | 3.775 Percent Reduction in SpO2 | Standard Deviation 1.5019 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Reduction of SpO2 Adjusted for Baseline | Day 8 | 3.286 Percent Reduction in SpO2 | Standard Deviation 1.7564 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose Reduction of SpO2 Adjusted for Baseline | Day 15 | 3.366 Percent Reduction in SpO2 | Standard Deviation 2.3449 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Reduction of SpO2 Adjusted for Baseline | Day 1 | 3.256 Percent Reduction in SpO2 | Standard Deviation 1.615 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Reduction of SpO2 Adjusted for Baseline | Day 8 | 2.751 Percent Reduction in SpO2 | Standard Deviation 1.765 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose Reduction of SpO2 Adjusted for Baseline | Day 15 | 2.757 Percent Reduction in SpO2 | Standard Deviation 1.7037 |
Secondary
Post-dose RR
Mean post-dose RR is reported.
Time frame: Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes the number of participants who were evaluable for the specified outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose RR | 13.577 Breaths/minute | Standard Deviation 2.0284 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose RR | 13.477 Breaths/minute | Standard Deviation 2.7037 |
Secondary
Post-dose SpO2
Mean post-dose SpO2 is reported.
Time frame: Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes the number of participants who were evaluable for the specified outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Post-dose SpO2 | 96.990 Percent SpO2 | Standard Deviation 1.6167 |
| Morphine Then Placebo Then Morphine + Placebo | Post-dose SpO2 | 97.900 Percent SpO2 | Standard Deviation 1.2076 |
Secondary
Renal Clearance (CLR) of AZD4041
The CLR of AZD4041 is reported.
Time frame: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041 and who were evaluable at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Renal Clearance (CLR) of AZD4041 | 0.04757 L/h | Geometric Coefficient of Variation 78.33 |
Secondary
Terminal Elimination Half-life (t1/2) of AZD4041
The t1/2 of AZD4041 is reported.
Time frame: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2) of AZD4041 | 14.48 Hour | Geometric Coefficient of Variation 111.7 |
Secondary
Terminal Elimination Half-life (t1/2λz) of AZD4041
The t1/2λz of AZD4041 are reported.
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2λz) of AZD4041 | Day 8 | 14.44 Hour | Geometric Coefficient of Variation 63.21 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2λz) of AZD4041 | Day 15 | 12.14 Hour | Geometric Coefficient of Variation 39.71 |
Secondary
Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites
The t1/2λz of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine (Day 1) | 3.131 Hour | Geometric Coefficient of Variation 49.58 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine (Day 15) | 3.090 Hour | Geometric Coefficient of Variation 32.23 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 10.04 Hour | Geometric Coefficient of Variation 62.79 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 11.13 Hour | Geometric Coefficient of Variation 40 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 10.16 Hour | Geometric Coefficient of Variation 118.2 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 10.82 Hour | Geometric Coefficient of Variation 34.77 |
| Morphine Then Placebo Then Morphine + Placebo | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 10.38 Hour | Geometric Coefficient of Variation 51.1 |
| Morphine Then Placebo Then Morphine + Placebo | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine (Day 1) | 3.493 Hour | Geometric Coefficient of Variation 53.29 |
| Morphine Then Placebo Then Morphine + Placebo | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 12.39 Hour | Geometric Coefficient of Variation 24.99 |
| Morphine Then Placebo Then Morphine + Placebo | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine (Day 15) | 4.483 Hour | Geometric Coefficient of Variation 109 |
| Morphine Then Placebo Then Morphine + Placebo | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 12.27 Hour | Geometric Coefficient of Variation 32.34 |
| Morphine Then Placebo Then Morphine + Placebo | Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 11.37 Hour | Geometric Coefficient of Variation 46.87 |
Secondary
Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites
The tlast of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine (Day 1) | 12.00 Hours |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine (Day 15) | 12.00 Hours |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 36.00 Hours |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 48.00 Hours |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 36.00 Hours |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 36.03 Hours |
| Morphine Then Placebo Then Morphine + Placebo | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 36.00 Hours |
| Morphine Then Placebo Then Morphine + Placebo | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine (Day 1) | 12.00 Hours |
| Morphine Then Placebo Then Morphine + Placebo | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 36.00 Hours |
| Morphine Then Placebo Then Morphine + Placebo | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine (Day 15) | 12.00 Hours |
| Morphine Then Placebo Then Morphine + Placebo | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 36.00 Hours |
| Morphine Then Placebo Then Morphine + Placebo | Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 36.00 Hours |
Secondary
Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg
Mean time to each increased EtCO2 episode of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) is reported.
Time frame: Day 1 and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes those participants who had EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). On Day 1, number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) was 0.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg | Day 15 | 2.812 Hours | Standard Deviation 1.6494 |
| Morphine Then Placebo Then Morphine + Placebo | Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg | Day 15 | 2.083 Hours | — |
| Unknown | Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg | Day 1 | — Hours | — |
Secondary
Time to Each Reduced Respiratory Rate Episode of < 6 Breaths/Min
Mean time to each reduced respiratory rate episode of \< 6 breaths/min (sustained for at least 30 seconds) is reported.
Time frame: Day 1, Day 8, and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants with RR of \< 6 breaths/min (sustained for at least 30 seconds) was 0.
Secondary
Time to Reach Maximum Observed Concentration at Steady State (Tmax,ss) of AZD4041
The tmax,ss of AZD4041 are reported.
Time frame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reach Maximum Observed Concentration at Steady State (Tmax,ss) of AZD4041 | Day 8 | 0.50 Hour |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reach Maximum Observed Concentration at Steady State (Tmax,ss) of AZD4041 | Day 15 | 1.57 Hour |
Secondary
Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites
The Tmax of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine (Day 1) | 0.08 Hour |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine (Day 15) | 0.08 Hour |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 0.25 Hour |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 0.27 Hour |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 0.76 Hour |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 1.00 Hour |
| Morphine Then Placebo Then Morphine + Placebo | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 1) | 0.50 Hour |
| Morphine Then Placebo Then Morphine + Placebo | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine (Day 1) | 0.08 Hour |
| Morphine Then Placebo Then Morphine + Placebo | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 15) | 0.27 Hour |
| Morphine Then Placebo Then Morphine + Placebo | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine (Day 15) | 0.08 Hour |
| Morphine Then Placebo Then Morphine + Placebo | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine-6-glucuronide (Day 15) | 0.50 Hour |
| Morphine Then Placebo Then Morphine + Placebo | Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites | Morphine-3-glucuronide (Day 1) | 0.25 Hour |
Secondary
Time to Reduction in SpO2 to < 92%
Mean time to reduction from baseline in SpO2 to \< 92% (sustained for at least 30 seconds) is reported.
Time frame: Day 1 and Day 15
Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes only those participants who had reduction in SpO2 to \< 92% (sustained for at least 30 seconds). On Day 1, number of participants with reduction in SpO2 to \< 92% (sustained for at least 30 seconds) was 0.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Time to Reduction in SpO2 to < 92% | Day 15 | 0.986 Hours |
| Unknown | Time to Reduction in SpO2 to < 92% | Day 1 | — Hours |
Secondary
Total Body Clearance (CL) of Morphine
The CL of morphine are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Total Body Clearance (CL) of Morphine | Day 1 | 142.4 L/h | Geometric Coefficient of Variation 26.3 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Total Body Clearance (CL) of Morphine | Day 15 | 140.2 L/h | Geometric Coefficient of Variation 28.33 |
| Morphine Then Placebo Then Morphine + Placebo | Total Body Clearance (CL) of Morphine | Day 1 | 149.4 L/h | Geometric Coefficient of Variation 21.19 |
| Morphine Then Placebo Then Morphine + Placebo | Total Body Clearance (CL) of Morphine | Day 15 | 142.0 L/h | Geometric Coefficient of Variation 17.87 |
Secondary
Volume of Distribution Based on the Terminal Phase (Vz) of Morphine
The Vz of morphine are reported.
Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites
Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Morphine Then AZD4041 Then Morphine + AZD4041 | Volume of Distribution Based on the Terminal Phase (Vz) of Morphine | Day 1 | 643.2 Liter | Geometric Coefficient of Variation 41.23 |
| Morphine Then AZD4041 Then Morphine + AZD4041 | Volume of Distribution Based on the Terminal Phase (Vz) of Morphine | Day 15 | 625.1 Liter | Geometric Coefficient of Variation 36.38 |
| Morphine Then Placebo Then Morphine + Placebo | Volume of Distribution Based on the Terminal Phase (Vz) of Morphine | Day 1 | 753.0 Liter | Geometric Coefficient of Variation 55.77 |
| Morphine Then Placebo Then Morphine + Placebo | Volume of Distribution Based on the Terminal Phase (Vz) of Morphine | Day 15 | 918.5 Liter | Geometric Coefficient of Variation 97.58 |